Pharmaceutical compositions containing a bis-(dihydroxy-phenyl-ethylol)-substituted alkylenediamine and-methods of using same

ABSTRACT

PHARMACEUTICAL COMPOSITIONS COMPRISING AS AN ACTIVE INGREDIENTS A COMPOUND OF THE FORMULA   ((2-R2,3,4-DI(HO-)PHENYL)-CH(-OH)-CH2-NH-C(-R1)2)2-(CH2)M   WHEREIN R1 IS HYDROGEN OR METHYL, R2 IS METHYL, METHOXY, ETHOXY OR CHLORINE AND, IF R1 IS METHYL, ADDITIONALLY HYDROGEN, AND M IS A WHOLE NUMBER FROM 0 TO 10, INCLUSIVE, OR A NON-TOXIC, PHAMACOLOGICALLY ACCEPTABLE ACID ADDITION SALT THEREOF; AND METHODS OF USING THE SAME AS UTERINE SPASMOLYTICS, ANTIPRUTITICS, VASODILATORES AND ANTIALLERGIC.

3,769,430 O Patented 0, 1973 easily removable by hydrolysis or hydrogenation, pref- 3,769,430 erably benzyl, acyl or, together with each other and the PHARMACEUTICAL COMPOSITIONS CONTAIN- d' t t d ING A B S (DIH DROX PHENY ETHYLon 1th eln gygen a ogisiianacietall ra ical, such as diphenyl SUBSTITUTED ALKYLENEDIAMINE AND- m y ene an is y or benzyl' METHODS OF USING SAME 5 The reductlon may be effected either by catalytic hydro- Kurt Schmmm Anton Mentmp Karl zeile and EmSt genat1on using the customary platinum, palladium or Raney nickel catalysts, or with the aid of complex hy- Otto Renth, Ingelheim am Rhein, Albrecht Engelhardt, Mainz, and Werner Traunecker, Munster-Sarmsheim, drides, such as sodium borohydride or lithium aluminum Germany, assignors to Boehringer Ingelheim G.m.b.H., y of also y means of the m d r Ingelheim am Bhein, Germany Verley Reduction (aluminum alkoxide reduction). N0 Drawing. Original application Dec. 2, 1969, Ser. No. If the protective groups are not already split olf during 881606 now Patent No. 3673187 dated June 27 th d ti th ma ub 6 m1 b b 1972. D ivided and this appliatio n Ma 12, 1972, Ser: tomary method, y y s S que y e removed y Gus 252,615 Int Cl A611 27/00 A starting compound of the Formula II may be ob- Us. CL 424 330 10 Claims tained, for example, by reacting a compound of the formula ABSTRACT OF THE DISCLOSURE m 0 Pharmaceutical compositions comprising as an active R'0-iiomx ingredient a compound of the formula (In) HO R1 R2 OH r r r a no-- CH-GHz-NHC(OH2)m-(E-NH-CHQOH OH in R1 wherein wherein R has the same meanings as in Formula I, R has the same meanings as in Formula II, and X is chlorine R1 is hydrogen or methyl or bromine, with an alkylenediamine of the formula R is methyl, methoxy, ethoxy or chlorine and, if R is methyl, additionally hydrogen, and m is a whole number from 0 to 10, inclusive,

or a non-toxic, pharmacologically acceptable acid addition R1 R1 salt thereof; and methods of using the same as uterine spasmolytics, antipruritics, vasodllators and antiallergics. l

1 R1 (IV) This is a division of copending application Ser. No. 881,606, filed Dec. 2, 1969', now US. Patent No. 3,673,- 187, issued June 27, 1972. wherein R and m have the same meanings as in Formula This invention relates to novel pharmaceutical com- 40 I, and has the Same meanings as in Formula i the positions containing as an active ingredient an N,N'-bis- Presence of a condensation agent, $11011 as Potassium (dih d h p th l l)- 1k 1 di in a onto i bonate, or of an excess of diamine IV above the stoichioacid addition salt thereof, as well as to methods of using metric amount required for reaction with Compound III. the same. Racemic mixtures of the compounds of the Formula I More particularly, the present invention relates to may be separated into their individual stereoisomeric compharmaceutical compositions containing as an active inponents by customary methods.

gredient a compound of the formula The bis-substituted alkylenediamines represented by R OH HO B2 II R] 11 2 HO- -CHOHCH2HN-(F(CHz)m+-NHCHz-CH OH wherein Formula I are organic bases and therefore form acid addition salts with inorganic or organic acids. Examples of R1 hydrogen or methyl non-toxic, pharmacologically acceptable acid addition salts R2 15 methyl Ff ethoxy or chlorine 1f R1 are those formed with hydrochloric acid, hydrobromic E addltlonany hydrogen and acid, sulfuric acid, phosphoric acid, acetic acid, citric acid, m 15 an Integer from 0 to Preferably 2 to mcluswe tartaric acid, 8-chlorotheophylline or the like. Such acid addition salts are obtained by customary methods, such as by acidifying a solution of the free base with the desired inorganic or organic acid.

The following examples further illustrate the present or a non-toxic, pharmacologically acceptable acid addition salt thereof, in the form of a pure stereoisomer, a mixture of stereoisomers or a racemate.

A compound of the Formula I may be prepared by methods involving well known chemical principles, namely, invention and will enable others skilled in the art to by reducing a compound of the formula understand it more completely. It should be understood,

R R OR B O r r i R'OQ-iL-Cflz-NR?(CH2)mfi)NR"CHzC OR wherein R R and m have the same meanings as in Forhowever, that the invention is not limited solely to the mula I; R' is hydrogen or a protective group which is particular examples given below.

3 V 4 EXAMPLE 1 EXAMPLE 2 N,N'-bis- [18- (2'-ethoxy-3 '4'-dihydroxy-phenyl) -p-hydroxy-ethyl]-1,4-butylenediamine dihydrochloride dihydrochloride A mixture consisting of 270 gm. of 2,3,4-tri1hydroxi 6 Analogous to Example 1, 33%??? iif il fcifiii i s fm? %f 1lain e and Phenylmehylenedioxyacetophenoae Q) 338 gm of diPhenyl-dichlorc;methane was allowed to was prgpared from :12; z stand overnight at room temperature, and then a solution 233:2 i g i i g 'g 145 2 1L t fig i ifi fig: 0f 200 of Sodlum hydroxlde 500 of Water was butylenediarnine and gm. of sodium carbonate were N,N-bis- [B-(3',4'-dihydroxy-phenyl) -;8-hydroxy-ethyl]- 1,4-butylenediamine dihydrochloride added In Small P The reactlon Solunon was refluxed in ethanol for three hours. Thereafter, the reacahewed to t h for hours at mom temperatllre t tion mixture was vacuum-filtered, and the filtrate was was then ac dified wrth concentrated hydrochloric acid. evaporated The residue was dissolved in 300 of The erystalhhe Slurry formed thereby was vacuum 15 methanol, the solution Was acidified with ethereal hydro filtered, and the filter cake was washed first with water chloric acid and the acidic solution was h ydrogenated at P then Wlth methanol 249 of the 60 C. and 5 atmospheres pressure in the presence of dlphenylmethylenedloxy'acetophenone Z 155456 palladized charcoal as a catalyst, yielding N,N'-bis-[fi- C.) thus obtained were reacted at 40 with 288 ml. of ethoxy diphenylmethylenedioxy phenyl) dlmethyl'shlfate and 204 of Potasslum hydroxlde m B-oxo-ethyl]-1,4-butylenediamine dihydrochloride which methanoli 0 11 h Precipitated reactioh Product had a melting point of 208-210 C. after recrystallization was collected and admixed with ether, the m1xture was from acetonitri1e vacuum-filtered, and the filtrate was evaporated. The By boiling 23 gm of this product for 11/2 hours in 2-II16t110XY-3,4-diphehylmethylehedloxy'acetophenohe admixture with 140 ml. of methanol and 90 ml. of contained thereby bromlhated at m hehzehe 50111 25 centrated hydrochloric acid and thereafter distilling off tron. The solution was evaporated, and the raw a-bromothe methanol, z 2 methoxy 3,4 dlphenylrpethylenedgoxyacetophenone phenyl)-,B-oxo-ethyl]1,4-butylenediamine dihydrochloride thus obtained was recrystallized from lsopropanol (M.P. 227 230 c f o water/acetonitrile) was 137 C.). tained. This compound was hydrogenated at room tem- -5 of this brothoketohe were adthlxed Wlth 30 perature and atmospheric pressure in methanol in the g of N,N'-dibehZY1-1,4'h11ty1ehediamihe and 400 0t presence of platinum as a catalyst. After completion of a and the mixture Was feflhxei Thereafter, the the hydrogenation, the catalyst was filtered off, the filtrate reaction mixture was Va the filtrate Was was evaporated, and the residue was recrystallized from acidified with ethereal hydrochloric acid, and water was h l, yielding N,N' bi p (2'- h 3' 4' dih d added to the acidic solution until it began to become phenyl)-fl-hydroxy-ethyl]-1,4-butylenediamine dihydrocloudy. N,N'-dibenzyl-N,N'-bis-[,B-(3',4'-d1phenylmethylchloride, M.P. 180182 C., of the formula enedioxy 2' methoxy phenyl)-fl-oxoethyl]-1,;t-butyl- EXAMPLE 3 enediamine dih drochloride reci itate out; a ter re- I crystallization fr om acetonitrile it had a melting point of yl- 1h y y-p y )-p-h 196-198 c. 15 gm. of this compound were boiled for 90 dYOXYethYl]'Ltbutylenedmmme dlhydrochlonde minutes with a mixture consisting of 88.5 ml. of methanol A mixture consisting of 44 gm. of a-br m 3 4-dib and 61.5 ml. of concentrated hydrochloric acid, and the Zy1OXy 2 methy1 acetophenone 12 429 c breaction solution was allowed to cool, whereupon N,N'- mined by brominating 3 4. l .zh p dibehzyl bis [I hY Y' phenone (M.P. 90 C.) with bromine in benzene at 40 p y '1 -OXO-ethYI]-1,4-b11tY1el1ed1am1he dlhydrochle' C.], 13.4 gm. of N,N'-dibenzyl-1,4-butylenediamine, 200 ride fr0111Walter/ethanol) Precipitated ml. of ethanol, 75 ml. of acetonitrile and 15 gm. of so- Ollt- The precipitate was collected and then hydrogenated dium carbonate was refluxed for three hours. Thereafter, in a mixture of methan l and Water at the reaction mixture was vacuum-filtered, the filtrate was 5 atmospheres Pressure ill the Presence of Pahadlzed evaporated, the residue was dissolved in 300 ml. of methcharcoal as a catalyst, yielding N,N- i -[fi-( Y" anol, the solution was acidified with ethereal hydrochloric 3',4' dihydroxy phenyl) ,8 oxo ethyl]-1, y acid, and the acidic solution was hydrogenated at C. diamine dihydrochloride [M.P. 235-236" C. (decomp.), and 5 atmospheres pressure in the presence of palladized from water/acetonitrile]. charcoal as a catalyst. After completion of the hydro- This diketone was then hydrogenated in methanol at genation, the catalyst was vacuum-filtered 01f, the filtrate room temperature and atmospheric pressure in the was evaporated, and the residue, N,N-bis-[B-(2'-methylpresence of platinum as a catalyst, whereby N,N'-bis- 60 3(4 dihydroxy-phenyl) fi oxo-ethyl] 1,4 butylene- [l8 methoxy dih d o y-phenyl)-l3- ydIOXydiamine dihydrochloride, M.P. 268271 C. (decomp.),

ethyl] 1,4-butylenediamine dihydrochloride of the was recrystallized from water. This product was hydroformula genated in methanol at room temperature and atmos- H0 OCH; 01130 OH pheric pressure in the presence of platinum as a catalyst, were obtamed. After recrystallizatlon from methanol/ yi e1 din g [B (2, methy1 3,,4, dihydroxyphenyl) acetonitrile, the Product had a melting P 0t S-hydroxy-ethyl}1,4-butylenediamine dihydrochloride of 174 C. the formula HO OH: H O OH which had a melting point of 188-1 89 C. after recrystallization from water/acetone.

EXAMPLE 4 A mixture consisting of 42.5 gm. of a-brOmO-Z-rnethoxy 3,4 diphenylmethylenedioxy acetophenone (for preparation see Example 1), 14.8 gm. of N,N-dibenzyl- 1,6-hexylenediamine, gm. of sodium carbonate, 200 ml. of ethanol and 75 ml. of acetonitrile was refluxed for three hours. Thereafter, the reaction mixture was vacuum-filtered, the filtrate was evaporated, the residue was dissolved in 300 ml. of methanol, the solution was acidified with ethereal hydrochloric acid, and the acidic solution was hydrogenated at 60 C. and 5 atmospheres pressure in the presence of palladized charcoal. After completion of the hydrogenation the catalyst was vacuum-filtered off, the filtrate was evaporated, and the residual N,N'-bis- [p- (2' methoxy 3',4' diphenyl methylenedioxy phenyl)-;3-oxo-ethyl]-1,6-hexylenediamine, M.P. 218-222 C. (decomp.) was crystallized from acetonitrile.

A mixture was 19 gm. of this crystalline product, 78 ml. of concentrated hydrochloric acid and 112 ml. of methanol was refluxed for 90 minutes and yielded N,N'- bis [/8 (2 methoxy 3',4 dihydroxy phenyl) 3- oxo-ethyl]-1,6-hexylenediamine dihydrochloride (M.P.

HO CH3 258-259 C., from water), which was hydrogenated in methanol at room temperature and atmospheric pressure in the presence of platinum as a catalyst. After completion of the hydrogenation the catalyst was vacuum-filtered off, and the methanol was evaporated, whereby N,N-bis- [[3 (2' methoxy 3',4 dihydroxy phenyl) 9 hydroxy-ethyl]1,6-hexylenediamine dihydrochloride of the formula HO 0 CH CH (I) pared by Ibrominating 3,4-dimethoxy-Z-methyl-acetophenone in ether), 26.5 gm. of 2,5-dimethyl-2,S-diaminohexane, 300 ml. of ethanol and 55 gm. of sodium carbonate was refluxed for three hours. Thereafter, the reaction mixture was vacuum filtered, the filtrate was evaporated, the residue was dissolved in 300 ml. of ether, and the solution was extracted twice with water, dried with sodium sulfate and evaporated. The oily residue was dissolved in 150 ml. of acetonitrile, the resulting solution was acidified with ethereal hydrochloric acid, and the N,N-bis-[ 8-(3',4'-dimethoxy 2 methyl-phenyD-fi-oxoethyl] 2,5 dimethyl 2,5 diamino-hexane dihydrochloride precipitated thereby was collected and recrystallized from water, whereupon it had a melting point of 213-217 C. This product was boiled with 48% hydrobromic acid, yielding N,N bis [/3-(3',4-dihydroxy-2- methyl-phenyl)-/3-oxo-ethyl] 2,5-dimethyl-2,5-diaminohexane dihydrobromide, which was converted into the free base by treatment with aqueous ammonia and subsequently into the dihydrochloride (M.P. 220-230" C.) with ethereal hydrochloric acid. Catalytic hydrogenation of this dihydrochloride in methanol at room temperature and atmospheric pressure in the presence of platinum as a catalyst yielded N,N'-bis-[B-(2-methyl-3',4'-dihydroxy-phenyl) ,B hydroxy-ethyl]-2,5-dimethyl-2,5-diaminohexane dihydrochloride, M.P. 176-178 C., of the formula N,N'-bis-[fl-(3,4-dihydroxy-phenyl)-fll-hydroxy-ethyl]- 2,5-dimethyl-2,S-diamino-hexane dihydrochloride A mixture consisting of 41.1 gm. of ot-IbrOrnO-3,4-dibenzyloxy-acetophenone [M.P. 90-92 C., prepared by brominating 3,4-dibenzyloxy-acetophenone (M.P. 9697 C.), in benzene at 50 C.], 7.2 gm. of 2,5-dimethyl-2,5-

was obtained which had a melting point of 176-178 C. diamino-hexane, 15 gm. of sodium carbonate, 200 ml. of

after recrystallization from water/isopropanol.

EXAMPLE 5 droxy-ethyl]-1,8-diamino-octane dihydrochloride Using a procedure analogous tothat described in Example 4, N,N'-bis-[fl-(2'-methoxy-3',4'-dihydroxy-phenyl)-fl-hydroxy-ethyl]-1,8-diamino-octane dihydrochloride, M.P. 121-124 C. (from ethanol/ether), of the formula HO OCHa EXAMPLE 6 N,N'-bis-[B-(2'-methyl 3' 4' dihydroxy-phenyD-fihydroxy-ethyl] 2,5 dimethyl 2,5 diamino-hexane dihydrochloride A mixture consisting of 100 gm. of a-bromo-3,4-dimethoxy-Z-methyl-acetophenone (M.P. 87-89 C., pre

ethanol and 20 ml. of acetonitrile was refluxed for four hours. Thereafter, the reaction mixture was vacuumfiltered, the filtrate was evaporated, the residue was dissolved in 100 ml. of ether, and the resulting solution was extracted twice with 100 ml. of water, dried with sodium sulfate and evaporated. The residue was dissolved in 50 ml. of acetonitrile, the resulting solution was acidified with ethereal hydrochloric acid, and the N,N-bis-[fi-(3',- 3'-dibenzyloxy-phenyl)-/3-oxo-ethyl]-2,5 dimethyl 2,5-

diamino-hexane dihydrochloride precipitated thereby was collected and recrystallized from ethylacetate/ether, whereupon it had a melting point of 221-226 C. The dihydrochloride was converted into the free base with dilute ammonia, the base was dissolved in 300 ml. of ethanol, and the solution was reduced with sodium borohydride, whereby N,N'-bis-[fl-(3',4-dibenzyloxy-phenyl)- B-hydroxy-ethyl]-2,5-dimethyl-2,S-diamino-hexane gradually precipitated out. The free base was dissolved in acetonitrile, the solution was acidified with ethereal hydrochloric acid, and the dihydrochloride (M.P. 202-205 C.) was precipitated by addition of water to the acidic solution. The dihydrochloride was collected and catalytically hydrogenated in methanol in the presence of palladized charcoal at room temperature and atmospheric pressure, yielding N,N'-bis[(3-(3',4'-dihydroxy-phenyl)-fihydroxyethyl]2,5 dimethyl-2,S-diaminohexane dihydrochloride of the formula H3 H3 which had a melting point of 228 C. after recrystallization from water/acetom'trile.

EXAMPLE 8 N,N'-bis- [/3- (2-chloro-3',4'-dihydroxy-phenyl -B-hydroxyethyl] 1,6-diamino-hexane dihydrochloride A mixture consisting of 21.5 gm. of a-bromo-2-chloro- 3,4-dibenzyloxy-acetophenone (M.P. 98 C.), 7.4 gm. of N,N-dibenzyl-1,6-diamino-hexane, 7.5 gm. of sodium carbonate, 100 ml. of ethanol and 30 ml. of acetonitrile was refluxed for three hours. Thereafter, the reaction mixture was vacuum-filtered, the filtrate was evaporated, the residue was dissolved in ethyl acetate, the solution was acidified with ethereal hydrochloric acid, and the precipitated N,N bis-[fi -(2'-chloro-3,4'-dibenzyloxy-phenyl)-/3-oxoethyIJ-lfi-diamino-hexane dihydrochloride (M.P. 7580 C.) was collected and transformed into the free base with dilute ammonia. The free .base was dissolved in a mixture of ethanol and dioxane, and the solution was reduced with sodium borohydride to yield N,N-bis-[fi-(2'-chloro- 3',4'-benzyloxy-phenyl) 3 hydroxy-ethyl]-1,6-diaminohexane, which was converted into its dihydrochloride (M.P. 98-103 C.) in acetonitrile-ethylacetate solution by means of ethereal hydrochloric acid. The dihydrochloride was catalytically hydrogenated under standard conditions in the presence of Raney nickel as a catalyst, yielding N,N' bis-[,8-(2'-chloro-3,4'-dihydroxy-phenyl)- p-hydroxy-ethyl]-1,6-diamino-hexane dihydrochloride of the formula HO Cl which had a melting point of l90-193 C. after recrystallization from water/ acetone.

The compounds embraced by Formula I above and their non-toxic, pharmacologically acceptable acid addition salts, have useful pharmacodynamic properties. More particularly, they exhibit long-lasting broncho-spasmolytic activities in warm-blooded animals without, at the same time, producing the undesirable side-efiects-especially undesirable effects upon the heartusually produced by known broncho-spasmolytics of related structure, such as N,N-bis-[p-(3',4' dihydroxy-phenyl)-fl-hydroxy-ethyl1- alkylenediamines. In addition, the compounds according to the present invention produce a spasmolytic action upon the uterus and also exhibit antipruritic, vasodilating and antiallergic activities in warm-blooded animals, such as mice, rats, dogs, cats or guinea pigs.

For pharmaceutical purposes the compounds of the Formula I or their non-toxic, acid addition salts are administered to warm-blooded animals perorally, parenterally or topically as active ingredients in customary pharmaceutical compositions, that is, compositions consisting essentially of an inert pharmaceutical carrier and an effective amount of the active ingredient, such as tablets, coated pills, capsules, aerosols, ointments, tinctures or solutions.

One efiective dosage unit of the compounds of the Formula I or their non-toxic acid addition salts for oral administration is from 0.083 to 0.84 mgm./kg.

Their effective concentration for topical administration is from 0.1 to 5%, based on the total weight of the topical composition.

on. on, no CHOH-CH -HN-i-(CHQg-i-NH-CH -CHOH 011-21101 Finally, the effective concentration for inhalation aerosol compositions is 0.1 to 5%, based on the total weight of the aerosol.

The following examples illustrate a few pharmaceutical compositions according to the present invention comprising a compound of the Formula I or a non-toxic acid addition salt thereof as an active ingredient, and represent the best mode contemplated of putting the invention into practical use. The parts are parts by weight unless otherwise specified.

EXAMPLE 9 Tablets The tablet composition was compounded from the following ingredients:

Parts N,N'-bis- [B-(2'-methoxy-3',4'-dihydroxy phenyl) S-hydroxy-ethyl]-1,4-diamino butane dihydrochloride 20.0 Stearic acid 6.0 Dextrose 574.0

Total 600.0

Compounding procedure: The ingredients were intimately admixed with each other, and the mixture was compressed into 600 mgm.-tablets. Each tablet contained 20 mgm. of the diamino-butane compound, and, when administered perorally to a warm-blooded animal of about 60 kg. body Weight in need of such treatment, produced very good broncho-spasmolytic effects.

EXAMPLE 10 Ointment The ointment was compounded from the following ingredients:

Parts p-hydroxy-ethyl}1,6-diamino-hexane dihydrochloride 0.200 Fuming hydrochloric acid 0.011 Sodium pyrosulfate 0.050

Mixture of equal parts by volume of cetyl alcohol and stearyl alcohol 18.000 White vaseline 5.000 Synthetic bergamot oil 0.075

Distilled water q.s.ad 100.000 parts.

Compounding procedure: The individual ingredients were admixed and processed in customary fashion into an ointment. Topically applied, the ointment was an effective antipruritic.

EXAMPLE l1 Inhalation aerosol The aerosol composition was compounded from the following ingredients:

Parts hydroxy-ethyl]-2,5-dimethyl-2,5 diaminohexane dihydrochloride 0.20 Soybean lecithin 0.05 Propellent gas mixture (trichlorofluoromethane, di-

chlorodifiuoromethane and cryofluorane) q.s.ad 1

100.00 parts.

Compounding procedure: The ingredients were admixed and filled under pressure or deep refrigeration into an aerosol container provided with a metering valve, which released an amount of aerosol spray containing about 1.0 mgm. of the diaminohexane compound each time it was actuated. One metered dose of this spray, inhaled into the respiratory tract of an adult warmblooded animal, in need of such treatment, produced very good broncho-spasmolytic elfects.

Analogous results were obtained when an equal amount of any other compound of Formula I or a non-toxic acid addition salt thereof was substituted for the particular diaminobutane or diaminohexane compound in illustrative Examples 9 to 11. Likewise, the amount of active ingredient in these examples may be varied to achieve the dosage unit range set forth above, and the amounts and nature of the inert pharmaceutical carrier ingredients may be varied to meet particular requirements.

While the present invention has been illustrated with the aid of certain specific embodiments thereof, it will be readily apparent to others skilled in the art that our invention is not limited to these particular embodiments, and that various changes and modifications may be made Without departing from the spirit of the invention or the scope of the appended claims.

We claim:

1. A pharmaceutical composition consisting essentially of an inert pharmaceutical carrier and an eifective 5. A composition according to claim 1, wherein said compound is N,N-bis-[B-(2-methoxy-3',4 dihydroxyhenyD-fi-hydroxy-ethyl]-l,6-diamino-hexane or a nontoxic, pharmacologically acceptable acid addition salt thereof.

6. A composition according to claim 1, wherein said compound is N,N'-bis-[B-(2methoxy-3',4'-dihydroxyphenyl)-/3-hydroxy-ethyl]-l,8-diamino-octane or a nontoxic, pharmacologically acceptable acid addition salt thereof.

7. A composition according to claim 1, wherein said compound is N,Nbis-[ 8-(2'-methyl 3,4 dihydroxyphenyD-fi-hydroxy-ethyl]2,5-dimethyl 2,5 diaminohexane or a non-toxic, pharmacologically acceptable acid addition salt thereof.

8. A composition according to claim 1, wherein said compound is N,N-bis-[fi-(3',4'-dihydroxy-phenyl)-fi-hydroxy-ethyl]-2,5-dimethyl-2,S-diamino-hexane or a nontoxic, pharmacologically acceptable acid addition salt thereof.

9. A composition according to claim 1, wherein said compound is N,N'-bis-[fi-(2'-chloro 3',4' dihydroxyphenyl)-B-hydroxy-ethyl]-1,6-diamino-hexane or a nontoxic, pharmacologically acceptable acid addition salt thereof.

10. The method of alleviating bronchial spasms in a warm-blooded animal, which comprises administering to said animal an effective broncho-spasmolytic amount of a racemic or optically active compound of the formula HO R, R, OH

I l R1 110- CHoH-cHt-HNtfoH,).,,-NH-0H:0HOH+ 0H t 1 broncho-spasmolytic amount of a racemic or optically active compound of the formula HO R R OH I a $4 l HooH0H-cH,-HN -(0H,)m-o-NH JHlCHOH wherein wherein R is hydrogen or methyl,

R is methyl, methoxy, ethoxy or chlorine and, if R is methyl, also hydrogen, and

m is an integer from 2 to 6, inclusive,

R is hydrogen or methyl,

R is methyl, methoxy, ethoxy or chlorine and, if R, is

methyl, also hydrogen, and

m is an integer from 2 to 6, inclusive,

or a non-toxic pharmacologically acceptable acid addition salt thereof.

References Cited UNITED STATES PATENTS 7/1967 Schmid et a1 424330 ALBERT T. MEYERS, Primary Examiner N. A. DREZIN, Assistant Examiner U.S. Cl. XR. 

